Samuel John Rodgers

• Lapao, Ana Sofia Da Silva; Johnson, Lauren Sophie; Moncho, Laura Cristina Trachsel; Rodgers, Samuel J; Singh, Sakshi & Ng, Matthew [Vis alle 9 forfattere av denne artikkelen] (2025). The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism. eLIFE. 14. doi: 10.7554/elife.105541. Fulltekst i vitenarkiv Vis sammendrag

  SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.

• Ooms, Lisa M.; Ferguson, Daniel T.; Rodgers, Samuel J.; Sukhija, Karmanpreet K.; Jones, Emily I. & Csolle, Mariah P. [Vis alle 12 forfattere av denne artikkelen] (2025). Non-redundant roles of the phosphoinositide phosphatases PTEN and PIPP in PI3K/AKT signaling in breast cancer. Communications Biology. doi: 10.1038/s42003-025-09364-2. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Phosphoinositide 3-kinase (PI3K) signaling is hyperactivated in ~70% of breast cancers via mutations in oncogenes including PIK3CA or inactivation/depletion of phosphoinositide (PI)-phosphatases. Generation of PI(3,4,5)P 3 by PI3K activates many downstream effectors, including AKT, that induce cellular proliferation in breast cancer. In this context PI(3,4,5)P 3 is tightly regulated by PI-phosphatases, including the tumor suppressor PTEN and inositol polyphosphate 5-phosphatases such as PIPP/INPP5J. PTEN and PIPP dephosphorylate PI(3,4,5)P 3 to form different lipid products, thereby individually regulating AKT activation. PI3K/AKT signaling is complex and the functional interplay between these PI-phosphatases in suppressing this pathway in vivo is unknown. Here, we utilize experimental models of breast cancer, both dependent and independent of PIK3CA mutation. Pipp ablation in Pten +/− mice increases mammary AKT signaling and cell proliferation, associated with increased hyperplasia and ductal thickening, characteristics linked with mammary epithelial cell transformation. In breast cancer cell lines, combined PIPP / PTEN knockdown increases AKT signaling and cell proliferation, independent of mutant PIK3CA , above any single PI-phosphatase knockdown. Notably, combined PIPP/PTEN loss is observed in a subset of human breast cancers, associated with reduced survival. Collectively, these findings support a model whereby loss of PIPP constitutes a co-operative step towards breast cancer progression in the context of PTEN deficiency.

• Rodgers, Samuel John; Mitchell, Christina A. & Ooms, Lisa M. (2023). The mechanisms of class 1A PI3K and Wnt/β-catenin coupled signaling in breast cancer. Biochemical Society Transactions. ISSN 0300-5127. 51(4), s. 1472–1472. doi: 10.1042/bst20220866. Fulltekst i vitenarkiv Vis sammendrag

  The class IA PI3K signaling pathway is activated by growth factor stimulation and regulates a signaling cascade that promotes diverse events including cell growth, proliferation, migration and metabolism. PI3K signaling is one of the most commonly hyperactivated pathways in breast cancer, leading to increased tumor growth and progression. PI3K hyperactivation occurs via a number of genetic and epigenetic mechanisms including mutation or amplification of PIK3CA, the gene encoding the p110α subunit of PI3Kα, as well as via dysregulation of the upstream growth factor receptors or downstream signaling effectors. Over the past decade, extensive efforts to develop therapeutics that suppress oncogenic PI3K signaling have been undertaken. Although FDA-approved PI3K inhibitors are now emerging, their clinical success remains limited due to adverse effects and negative feedback mechanisms which contribute to their reduced efficacy. There is an emerging body of evidence demonstrating crosstalk between the PI3K and Wnt/β-catenin pathways in breast cancer. However, PI3K exhibits opposing effects on Wnt/β-catenin signaling in distinct tumor subsets, whereby PI3K promotes Wnt/β-catenin activation in ER+ cancers, but paradoxically suppresses this pathway in ER− breast cancers. This review discusses the molecular mechanisms for PI3K–Wnt crosstalk in breast cancer, and how Wnt-targeted therapies have the potential to contribute to treatment regimens for breast cancers with PI3K dysregulation.

• York, Harrison M.; Joshi, Kunaal; Wright, Charles S.; Kreplin, Laura Z.; Rodgers, Samuel J. & Moorthi, Ullhas K. [Vis alle 11 forfattere av denne artikkelen] (2023). Deterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism. Nature Communications. 14(1). doi: 10.1038/s41467-023-40428-1. Fulltekst i vitenarkiv Vis sammendrag

  Endosomal maturation is critical for robust and timely cargo transport to specific cellular compartments. The most prominent model of early endosomal maturation involves a phosphoinositide-driven gain or loss of specific proteins on individual endosomes, emphasising an autonomous and stochastic description. However, limitations in fast, volumetric imaging long hindered direct whole cell-level measurements of absolute numbers of maturation events. Here, we use lattice light-sheet imaging and bespoke automated analysis to track individual very early (APPL1-positive) and early (EEA1-positive) endosomes over the entire population, demonstrating that direct inter-endosomal contact drives maturation between these populations. Using fluorescence lifetime, we show that this endosomal interaction is underpinned by asymmetric binding of EEA1 to very early and early endosomes through its N- and C-termini, respectively. In combination with agent-based simulation which supports a ‘trigger-and-convert’ model, our findings indicate that APPL1- to EEA1-positive maturation is driven not by autonomous events but by heterotypic EEA1-mediated interactions, providing a mechanism for temporal and population-level control of maturation.

• Rodgers, Samuel J.; Jones, Emily I.; Mitchell, Christina A. & McGrath, Meagan J. (2022). Sequential conversion of PtdIns3P to PtdIns(3,5)P via endosome maturation couples nutrient signaling to lysosome reformation and basal autophagy. Autophagy. ISSN 1554-8627. 19(4), s. 1367–1367. doi: 10.1080/15548627.2022.2124499. Fulltekst i vitenarkiv
• Nanayakkara, Randini; Gurung, Rajendra; Rodgers, Samuel J.; Eramo, Matthew J.; Ramm, Georg & Mitchell, Christina A. [Vis alle 7 forfattere av denne artikkelen] (2022). Autophagic lysosome reformation in health and disease. Autophagy. ISSN 1554-8627. 19(5), s. 1395–1395. doi: 10.1080/15548627.2022.2128019. Fulltekst i vitenarkiv
• Rodgers, Samuel J.; Ooms, Lisa M. & Mitchell, Christina A. (2022). The FDA-Approved Drug Pyrvinium Selectively Targets ER+ Breast Cancer Cells with High INPP4B Expression. Cancers. 15(1), s. 135–135. doi: 10.3390/cancers15010135. Fulltekst i vitenarkiv Vis sammendrag

  The majority of breast cancers are estrogen receptor-positive (ER+), and endocrine therapies that suppress ER signaling are the standard-of-care treatment for this subset. However, up to half of all ER+ cancers eventually relapse, highlighting a need for improved clinical therapies. The phosphoinositide phosphatase, INPP4B, is overexpressed in almost half of all ER+ breast cancers, and promotes Wnt/β-catenin signaling, cell proliferation and tumor growth. Here, using cell viability assays, we report that INPP4B overexpression does not affect the sensitivity of ER+ breast cancer cells to standard-of-care treatments including the anti-estrogen 4-hydroxytamoxifen (4-OHT) or the PI3Kα inhibitor alpelisib. Examination of four small molecule Wnt inhibitors revealed that ER+ breast cancer cells with INPP4B overexpression were more sensitive to the FDA-approved drug pyrvinium and a 4-OHT-pyrvinium combination treatment. Using 3D culture models, we demonstrated that pyrvinium selectively reduced the size of INPP4B-overexpressing ER+ breast cancer spheroids in the presence and absence of 4-OHT. These findings suggest that repurposing pyrvinium as a Wnt inhibitor may be an effective therapeutic strategy for human ER+ breast cancers with high INPP4B levels.

• Rodgers, Samuel J; Jones, Emily I; Arumugam, Senthil; Hamila, Sabryn A; Danne, Jill & Gurung, Rajendra [Vis alle 11 forfattere av denne artikkelen] (2022). Endosome maturation links PI3Kα signaling to lysosome repopulation during basal autophagy. EMBO Journal. ISSN 0261-4189. 41(19). doi: 10.15252/embj.2021110398. Fulltekst i vitenarkiv Vis sammendrag

  Autophagy depends on the repopulation of lysosomes to degrade intracellular components and recycle nutrients. How cells co‐ordinate lysosome repopulation during basal autophagy, which occurs constitutively under nutrient‐rich conditions, is unknown. Here, we identify an endosome‐dependent phosphoinositide pathway that links PI3Kα signaling to lysosome repopulation during basal autophagy. We show that PI3Kα‐derived PI(3)P generated by INPP4B on late endosomes was required for basal but not starvation‐induced autophagic degradation. PI(3)P signals were maintained as late endosomes matured into endolysosomes, and served as the substrate for the 5‐kinase, PIKfyve, to generate PI(3,5)P2 . The SNX‐BAR protein, SNX2, was recruited to endolysosomes by PI(3,5)P2 and promoted lysosome reformation. Inhibition of INPP4B/PIKfyve‐dependent lysosome reformation reduced autophagic clearance of protein aggregates during proteotoxic stress leading to increased cytotoxicity. Therefore under nutrient‐rich conditions, PI3Kα, INPP4B, and PIKfyve sequentially contribute to basal autophagic degradation and protection from proteotoxic stress via PI(3,5)P2 ‐dependent lysosome reformation from endolysosomes. These findings reveal that endosome maturation couples PI3Kα signaling to lysosome reformation during basal autophagy.

• Rodgers, Samuel J.; Hamila, Sabryn A.; Mitchell, Christina A. & Ooms, Lisa M. (2021). A late endosome signaling hub that couples PI3Kα and WNT/β-catenin signaling in breast cancer. Molecular and Cellular Oncology (MCO). 8(4). doi: 10.1080/23723556.2021.1954470. Fulltekst i vitenarkiv
• Hamila, Sabryn A.; Ooms, Lisa M.; Rodgers, Samuel John & Mitchell, Christina A. (2021). The INPP4B paradox: Like PTEN, but different. Advances in Biological Regulation. ISSN 2212-4926. 82, s. 100817–100817. doi: 10.1016/j.jbior.2021.100817. Fulltekst i vitenarkiv
• Rodgers, Samuel John; Ooms, Lisa M.; Oorschot, Viola M. J.; Schittenhelm, Ralf B.; Nguyen, Elizabeth V. & Hamila, Sabryn A. [Vis alle 21 forfattere av denne artikkelen] (2021). INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer. Nature Communications. 12(1). doi: 10.1038/s41467-021-23241-6. Fulltekst i vitenarkiv Vis sammendrag

  Abstract INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P 2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA -mutant ER + breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA -mutant ER + breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P 2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER + breast cancer via PI(3,4)P 2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

• Ma, Xiuquan; Zhang, Luxi; Song, Jiangning; Nguyen, Elizabeth; Lee, Rachel S. & Rodgers, Samuel John [Vis alle 16 forfattere av denne artikkelen] (2019). Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation. Nature Communications. 10(1). doi: 10.1038/s41467-018-08154-1. Fulltekst i vitenarkiv Vis sammendrag

  Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotate the regulated kinases. As an example, we identify 63 protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells. An integrated siRNA screen identifies nine kinases, including SGK1, as being essential for Src-induced transformation. Accordingly, we find that Src positively regulates SGK1 expression in triple negative breast cancer cells, which exhibit a prominent signalling network governed by Src family kinases. Furthermore, combined inhibition of Src and SGK1 reduces colony formation and xenograft growth more effectively than either treatment alone. Therefore, this approach not only provides mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies.

• Rodgers, Samuel John; Ferguson, Daniel T.; Mitchell, Christina A. & Ooms, Lisa M. (2017). Regulation of PI3K effector signalling in cancer by the phosphoinositide phosphatases. Bioscience Reports. ISSN 0144-8463. 37(1). doi: 10.1042/bsr20160432. Fulltekst i vitenarkiv Vis sammendrag

  Class I phosphoinositide 3-kinase (PI3K) generates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) at the plasma membrane in response to growth factors, activating a signalling cascade that regulates many cellular functions including cell growth, proliferation, survival, migration and metabolism. The PI3K pathway is commonly dysregulated in human cancer, and drives tumorigenesis by promoting aberrant cell growth and transformation. PtdIns(3,4,5)P3 facilitates the activation of many pleckstrin homology (PH) domain-containing proteins including the serine/threonine kinase AKT. There are three AKT isoforms that are frequently hyperactivated in cancer through mutation, amplification or dysregulation of upstream regulatory proteins. AKT isoforms have converging and opposing functions in tumorigenesis. PtdIns(3,4,5)P3 signalling is degraded and terminated by phosphoinositide phosphatases such as phosphatase and tensin homologue (PTEN), proline-rich inositol polyphosphate 5-phosphatase (PIPP) (INPP5J) and inositol polyphosphate 4-phosphatase type II (INPP4B). PtdIns(3,4,5)P3 is rapidly hydrolysed by PIPP to generate phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), which is further hydrolysed by INPP4B to form phosphatidylinositol 3-phosphate (PtdIns3P). PtdIns(3,4)P2 and PtdIns3P are also important signalling molecules; PtdIns(3,4)P2 together with PtdIns(3,4,5)P3 are required for maximal AKT activation and PtdIns3P activates PI3K-dependent serum and glucocorticoid-regulated kinase (SGK3) signalling. Loss of Pten, Pipp or Inpp4b expression or function promotes tumour growth in murine cancer models through enhanced AKT isoform-specific signalling. INPP4B inhibits PtdIns(3,4)P2-mediated AKT activation in breast and prostate cancer; however, INPP4B expression is increased in acute myeloid leukaemia (AML), melanoma and colon cancer where it paradoxically promotes cell proliferation, transformation and/or drug resistance. This review will discuss how PTEN, PIPP and INPP4B distinctly regulate PtdIns(3,4,5)P3 signalling downstream of PI3K and how dysregulation of these phosphatases affects cancer outcomes.

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