Talk abstracts
Talk on Tuesday 03:30-03:45pm submitted by Justin Middleton
The stress-inducible gene Atf3 in non-cancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis
Justin Middleton (MCDB), Yi Seok Chang (MCDB), Swati Jalgaonkar (MCDB), Tsonwin Hai (BCP, College of Medicine)
Abstract:
Cancers cells have intrinsic abnormalities that contribute to their malignance, but also coerce non-cancer host cells to help them progress and metastasize. Recently, we found that the stress-inducible transcription factor, ATF3, in non-cancer host cells of mice (host-ATF3) is necessary for cancer cells to efficiently metastasize to the lung. An emerging picture in the cancer field is that chemotherapy can produce a paradoxically pro-cancer effect, both by enhancing chemoresistance, and also by facilitating metastasis. As ATF3 is induced by chemotherapeutic agents, we examined whether a frontline chemotherapy drug, paclitaxel (PTX), can further enhance metastasis in an ATF3-dependent manner. We found that repeated treatments of PTX, despite decreasing the size of primary tumors, increases metastasis to the lung. Importantly, this phenotype is dependent on host-ATF3, as knock-out mice did not show PTX-exacerbated metastasis. We also show that tumor-associated macrophages and inflammatory monocytes may provide a mechanistic explanation for this effect. Finally, we demonstrate that a single dose of PTX or another chemotherapeutic agent, cyclophosphamide, several days prior to intravenous cancer cell injection enhances colonization of mouse lungs in a host-ATF3-dependent manner, suggesting that chemotherapy alters the sites of future metastases. Together, these data led us to propose that ATF3 is a critical regulator of chemotherapy-induced metastasis. Further study into the downstream effectors of ATF3 in our model may provide targets to improve the efficacy of chemotherapy.
Keywords: Metastasis, chemotherapy, stress