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Oncogenes and their role in shaping the tumor microenvironment

Dr. Sushil Kumar, University of Pennsylvania, USA

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The proto-oncogenes are essential for normal cell growth, but they permanently turn on cell proliferation when they mutate or amplify their expression. When this happens, the cell grows out of control, and it leads to cancer. The oncogenes drive tumor initiation, growth, metastasis, and drug-resistance. Their mechanism of carcinogenesis could be cell-intrinsic or cell-extrinsic. I try to find novel oncogenes and understand their mechanism of action to design targeted cancer therapies.

The cell-intrinsic mechanism of oncogenic signaling activates the cell survival pathways. We identified a proto-oncogene Dll1, a Notch ligand, promoting normal mammary gland development (Science 2018). The expression of Dll1 goes up in tumors and even more in metastatic tumors. Higher expression of Dll1 makes cells resistant to chemotherapy, whereas blocking of Dll1 significantly reduces tumor growth and metastasis in vivo (Oncogene 2019, Nature Communications 2021).

The cell-extrinsic oncogenic mechanism is where the interaction of tumor cells with stromal cells is crucial. The epithelial/tumor-stromal interactions are essential for normal development and cancer. In normal development, we found epithelial cells interact with macrophages (immune cells) and drives the mammary gland's growth (Science 2018). Likewise, we discovered how breast cancer cells recruit myeloid-derived suppressor cells (MDSC; immune cells), and their interactions help cancer cells to promote tumor growth and metastasis. Understanding these interactions intrigued us to target them for further investigation. The inhibition of these interactions resulted in decreased metastatic events in mouse models (JCI, 2018).

In conclusion, targeting the tumor microenvironment with a standard of care therapy (such as chemotherapy or radiotherapy) could be vital for treating patients. I plan to reveal additional oncogenes and mechanisms for cancer therapy.

Sushil Kumar et al., Dll1+ quiescent... Nature Communications (2021)
Sushil Kumar et al., Estrogen-dependent DLL1... Oncogene (2019)
Sushil Kumar et al., DeltaNp63-driven... The Journal of clinical investigation (2018)
Rumela Chakrabarti et al., Notch ligand Dll1 mediates cross-talk ... Science (2018)

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