UCSF

Metastasis is the process by which tumor cells spread from the primary tumor to distant organs and form secondary tumors. In breast cancer, over 90% of cancer-related deaths are due to metastatic recurrence, which can occur even decades after surgical removal of the primary tumor. Moreover, metastatic lesions are often resistant to anti-cancer therapies effective at curbing primary tumor growth, a fact underscoring the need for a deeper understanding of the biological processes governing metastasis.

In recent years, tumor cell autophagy has emerged as an attractive therapeutic target to thwart cancer progression. Autophagy (from the Greek for “self-eating”) is a highly conserved, intracellular catabolic program endowing tumor cells the ability to respond to and survive a wide variety of environmental stressors, including chemotherapies. Thus, anti-malarials, namely Hydroxychloroquine, have been repurposed as autophagy inhibitors in clinical trials for the treatment of advanced solid tumors, as they block lysosomal degradation of autophagosomal cargo. However, despite these advances in our understanding of autophagy and cancer pathogenesis, it remains unclear how autophagy inhibition impacts metastatic recurrence, the primary cause of death in breast cancer.

Here, I investigate the functional consequences of tumor cell autophagy inhibition during distinct stages of breast cancer progression and metastasis. While tumor cell autophagy inhibition in the primary tumor attenuates its growth, autophagy-inhibition in disseminated tumor cells paradoxically promotes outgrowth into macro-metastases. Moreover, surgically excised autophagy-deficient primary tumors exhibited a propensity to recur locally and at metastatic sites, suggesting that autophagy inhibition promotes tumor initiating capabilities. Mechanistically, I uncover that autophagy controls metastatic outgrowth of disseminated tumor cells via degradation of the autophagy-specific substrate and cargo receptor, NBR1. Upon accumulation in autophagy-deficient cells, NBR1 elicits the acquisition of basal and stem-like traits in a subpopulation of otherwise luminal tumor cells, endowing them with an increased propensity for metastatic growth. Moreover, I demonstrate that pharmacologically enforced induction of autophagy in tumor cells elicits the autophagic degradation of NBR1 and prevents disseminated tumor cells for forming overt metastases. Taken together, this work demonstrates that autophagic degradation of NBR1 is a potential therapeutic strategy for preventing metastatic recurrence in breast cancer.

Given that pharmacological autophagy inhibition will impair autophagy in all tissues, I investigate how systemic autophagy inhibition impacts organ homeostasis in cancer-free animals. I find autophagy-deficiency to induce profound perturbations to the growth and metabolic state of the animal. Autophagy-deficient animals exhibit decreases in weight and size which is underscored by decreases in adipose and lean mass as well as in bone area, mineral content and density. This general loss of tissue mass is not due to decreased nutritional consumption, suggesting that the ability to utilize nutrients is potently controlled by autophagy. Additionally, autophagy-deficiency elicits de novo beiging of adipose tissue in the mammary gland, evidenced by upregulation of UCP1, which is concomitant with loss of mature basal epithelial populations, marked by TP63 and CK14. Overall, these findings demonstrate the multi-faceted roles of autophagy in normal tissue function and cancer progression.