Abstract
Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance. Some of these phenotypes pre-exist in pre-treatment subclones that become dominant after chemotherapy, indicating selection for resistance phenotypes. Post-chemotherapy cancer cells are effectively treated with drugs targeting acquired phenotypes. These findings highlight cancer's ability to evolve phenotypically and suggest a phenotype-targeted treatment strategy that adapts to cancer as it evolves.
| Original language | English (US) |
|---|---|
| Article number | 1231 |
| Journal | Nature Communications |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2017 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
Combating subclonal evolution of resistant cancer phenotypes. / Brady, Samuel W.; McQuerry, Jasmine A.; Qiao, Yi; Piccolo, Stephen R.; Shrestha, Gajendra; Jenkins, David F.; Layer, Ryan M.; Pedersen, Brent S.; Miller, Ryan H.; Esch, Amanda; Selitsky, Sara R.; Parker, Joel S.; Anderson, Layla A.; Dalley, Brian K.; Factor, Rachel E.; Reddy, Chakravarthy B.; Boltax, Jonathan P.; Li, Dean Y.; Moos, Philip J.; Gray, Joe; Heiser, Laura; Buys, Saundra S.; Cohen, Adam L.; Johnson, W. Evan; Quinlan, Aaron R.; Marth, Gabor; Werner, Theresa L.; Bild, Andrea H.
In: Nature Communications, Vol. 8, No. 1, 1231, 01.12.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Combating subclonal evolution of resistant cancer phenotypes
AU - Brady, Samuel W.
AU - McQuerry, Jasmine A.
AU - Qiao, Yi
AU - Piccolo, Stephen R.
AU - Shrestha, Gajendra
AU - Jenkins, David F.
AU - Layer, Ryan M.
AU - Pedersen, Brent S.
AU - Miller, Ryan H.
AU - Esch, Amanda
AU - Selitsky, Sara R.
AU - Parker, Joel S.
AU - Anderson, Layla A.
AU - Dalley, Brian K.
AU - Factor, Rachel E.
AU - Reddy, Chakravarthy B.
AU - Boltax, Jonathan P.
AU - Li, Dean Y.
AU - Moos, Philip J.
AU - Gray, Joe
AU - Heiser, Laura
AU - Buys, Saundra S.
AU - Cohen, Adam L.
AU - Johnson, W. Evan
AU - Quinlan, Aaron R.
AU - Marth, Gabor
AU - Werner, Theresa L.
AU - Bild, Andrea H.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance. Some of these phenotypes pre-exist in pre-treatment subclones that become dominant after chemotherapy, indicating selection for resistance phenotypes. Post-chemotherapy cancer cells are effectively treated with drugs targeting acquired phenotypes. These findings highlight cancer's ability to evolve phenotypically and suggest a phenotype-targeted treatment strategy that adapts to cancer as it evolves.
AB - Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance. Some of these phenotypes pre-exist in pre-treatment subclones that become dominant after chemotherapy, indicating selection for resistance phenotypes. Post-chemotherapy cancer cells are effectively treated with drugs targeting acquired phenotypes. These findings highlight cancer's ability to evolve phenotypically and suggest a phenotype-targeted treatment strategy that adapts to cancer as it evolves.
UR - http://www.scopus.com/inward/record.url?scp=85032882687&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85032882687&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-01174-3
DO - 10.1038/s41467-017-01174-3
M3 - Article
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1231
ER -