Overarching challenge and patient population:

Our proposal will address the overarching challenge to "Determine why/how breast cancer cells lay dormant for years and then re-emerge (recurrence); determine how to eliminate dormant cells early." Detection of cancer cells that spread early from primary lesions (early disseminated tumor cells - DTCs) that are considered pre-invasive (for example DCIS) suggested that metastasis might be initiated by early DTCs much earlier than anticipated. Importantly, more than 60% of all breast cancer deaths occur due to metastasis that develop after the 5-year survival mark and after a clinical dormant asymptomatic disease phase. This late relapse is observed in patients carrying estrogen receptor positive luminal tumors and also in a fraction of ErbB2+ patients. Our work suggests that early DTCs are more prone to entering dormancy and may be the source of late relapses.

What do we propose?

We propose that studying "early" DTCs is key to understanding the shift toward delayed breast cancer relapse that we hypothesize is caused by dormant DTCs. Our new evidence identifies novel mechanisms regulating early dissemination and dormancy of tumor cells that lodge in secondary organs. This study has allowed us to identify a number of markers that when detected in the primary early lesions we propose will inform on early spread of cancer and others that can tell us if DTCs are dormant or ready to grow. We propose to use these markers to determine whether mammary gland resident macrophages help early-evolved tumor cells to spread. We will also use these markers to test whether when these early DTCs arrive to target organs, they must again interact with macrophages to grow metastasis.

What is innovative in our studies?

Our study is radically innovative, because it examines in mouse spontaneous cancer models fluorescently tagged dormant "early" and "late" DTCs and macrophages. This allows "seeing" these events in real time using high resolution imaging providing new ways to study metastatic growth. Further, we match our experimental model with clinical samples linked to early cancer spreading data. This will allow benchmarking our experimental findings in humans. Our study represents both a conceptual and technical leap forward because these concepts have never been mechanistically modeled. We reasoned that understanding these mechanisms would allow designing anti-solitary dormant DTC therapies. This could solve the problem of metastasis at its root, by maintaining the dormancy of DTCs or eliminating them completely.

How would patients benefit in the clinic?

The opportunity here is to harness this information to stop the macrophages and DTCs from forming niches that fuel metastasis. We anticipate that in the short term (~5 years) our team could test whether early dissemination markers are informative about progression to more aggressive forms of breast cancer or late relapse. The Condeelis team has successfully applied such knowledge to markers in invasive cancers. This is a short-term deliverable from our proposal. In the long term (>5 years), we will focus on exploiting the identified mechanisms to maintain DTCs dormant and/or kill dormant DTCs. Both strategies would have metastasis preventive possibilities. The Aguirre-Ghiso team has already successfully identified dormancy markers and pathways to maintain dormancy or eradicate dormant DTCs. Accomplishment of these goals would transform cancer treatment.