Metastasis is the main cause of cancer-patient mortality. Our laboratory studies what makes metastasis lethal and how we can successfully target metastases to improve outcomes for cancer patients. We study metastasis as a systemic disease, which involves the crosstalk between metastatic cancer cells and both the cancer-inhabiting and cancer-free organs of the body. By interrupting this crosstalk, we aim to target the key biological processes that sustain the growth and survival of metastases. Our group investigates two key areas of metastasis biology - the therapy resistance of metastatic tumors and the systemic effects of metastatic disease, both of which contribute to the lethality observed in metastatic cancers. Our work in these areas is briefly described below.

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(a) Therapy resistance underlies metastasis-induced lethality since relapse is almost inevitable following metastatic cancer treatment. By analyzing how adaptive mechanisms within metastatic tumors evolve with treatment, we identified a novel S100A9-ALDH1A1-retinoic acid (RA) signaling axis that promotes therapy resistance in brain metastases from EGFR-mutant lung cancer patients (Biswas et al.; Cancer Discovery, 2022). Our present work explores the mechanisms that promote targeted-therapy resistance in different metastatic organs in breast and lung cancer.

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(b) Metastasis-induced lethality is primarily attributed to vital organ dysfunction; however, it also results from the metabolic deregulation of organs that are free of cancer cells. Indeed, over 80% of metastatic cancer patients suffer from a debilitating loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with reduced tolerance to anti-neoplastic therapy, poor prognosis, and accelerated death in metastatic cancer patients, and it is thought to arise from the release of tumor factors into the circulation that deregulate host metabolism. To study the process of cachexia during metastatic disease, we generated metastatic mouse models of different cancer types that develop cachexia and identified a zinc transporter, ZIP14, as a marker and mediator of cachexia (Wang et al., Nature Medicine, 2018). We found that Zip14 expression is reliably induced in muscles in response to metastatic cancer cells anywhere in the body, suggesting that muscle tissue can detect the presence of cancer cells at the earliest stages of metastatic relapse. We are currently investigating the host-tumor interactions by which muscles “sense” and “respond” to the presence of metastatic cancer cells elsewhere in the body.

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We envision that understanding the biological mechanisms driving both therapy resistance and the early metastasis-induced molecular changes in muscle will inform the design of more effective and durable treatments for metastatic cancer patients.

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Highlights of our work are shown below.