TY - JOUR
T1 - Spontaneous metastasis xenograft models link CD44 isoform 4 to angiogenesis, hypoxia, EMT and mitochondria-related pathways in colorectal cancer
AU - Everest-Dass, Arun
AU - Nersisyan, Stepan
AU - Maar, Hanna
AU - Novosad, Victor
AU - Schröder-Schwarz, Jennifer
AU - Freytag, Vera
AU - Stuke, Johanna L.
AU - Beine, Mia C.
AU - Schiecke, Alina
AU - Haider, Marie Therese
AU - Kriegs, Malte
AU - Elakad, Omar
AU - Bohnenberger, Hanibal
AU - Conradi, Lena Christin
AU - Raygorodskaya, Maria
AU - Krause, Linda
AU - von Itzstein, Mark
AU - Tonevitsky, Alexander
AU - Schumacher, Udo
AU - Maltseva, Diana
AU - Wicklein, Daniel
AU - Lange, Tobias
N1 - Publisher Copyright:
© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2024/1
Y1 - 2024/1
N2 - Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial–mesenchymal transition (EMT) and decreased oxidative phosphorylation (OxPhos) in patients; opposite associations were found for isoform 3. Pan-CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced hypoxia-inducible factor-1α and CEACAM5 but increased E-cadherin expression. Mitochondrial genes and proteins were induced upon pan-CD44 kd, as were OxPhos genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis-promoting role of CD44 isoform 4.
AB - Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial–mesenchymal transition (EMT) and decreased oxidative phosphorylation (OxPhos) in patients; opposite associations were found for isoform 3. Pan-CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced hypoxia-inducible factor-1α and CEACAM5 but increased E-cadherin expression. Mitochondrial genes and proteins were induced upon pan-CD44 kd, as were OxPhos genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis-promoting role of CD44 isoform 4.
KW - CD44 isoforms
KW - HT-29
KW - colorectal cancer
KW - metastasis
UR - http://www.scopus.com/inward/record.url?scp=85175825183&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.13535
DO - 10.1002/1878-0261.13535
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C2 - 37849446
AN - SCOPUS:85175825183
SN - 1574-7891
VL - 18
SP - 62
EP - 90
JO - Molecular Oncology
JF - Molecular Oncology
IS - 1
ER -
